Method and system for determining settings for deep brain stimulation

ABSTRACT

A method and system are provided for determining a relation between stimulation settings for a brain stimulation probe and a corresponding V-field. The brain stimulation probe comprises multiple stimulation electrodes. The V-field is an electrical field in brain tissue surrounding the stimulation electrodes. The method comprises sequentially applying a test current to n stimulation electrodes, n being a number between 2 and the number of stimulation electrodes of the brain stimulation probe, for each test current at one of the n stimulation electrodes, measuring a resulting excitation voltage at m stimulation electrodes, m being a number between 2 and the number of stimulation electrodes of the brain stimulation probe, from the stimulation settings and the measured excitation voltages, deriving a coupling matrix, an element in the coupling matrix reflecting an amount of electrical impedance between two of the stimulation electrodes, and using the coupling matrix for determining the relation between the stimulation settings and the corresponding V-field.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/629,852 filed Jun. 22, 2017, now U.S. Pat. No. 10,758,727, which is acontinuation of U.S. patent application Ser. No. 14/556,847, filed Dec.1, 2014, now U.S. Pat. No. 9,717,912, which is a continuation of U.S.patent application Ser. No. 13/581,484, filed Oct. 9, 2012, now U.S.Pat. No. 8,929,992, which is a U.S. National Stage of InternationalPatent Application No. PCT/IB2011/050809, filed Feb. 25, 2011, whichclaims priority to U.S. Provisional Patent Application No. 61/309,074,filed Mar. 1, 2010, each of which is incorporated herein by reference inits entirety.

FIELD OF THE INVENTION

This invention relates to a method for determining a relation betweenstimulation settings for a brain stimulation probe and a correspondingV-field, the brain stimulation probe comprising multiple stimulationelectrodes, the V-field being a potential distribution in brain tissuesurrounding the stimulation electrodes.

This invention further relates to a computer program product and to acontrol system for determining such a relation.

BACKGROUND OF THE INVENTION

Deep brain stimulation (DBS) is a surgical treatment involving theimplantation of a medical device, which sends electrical pulses tospecific parts of the brain. A preferred DBS probe comprises a pluralityof electrodes for providing stimulating electrical pulses at differentpositions in the target region. For example, the probe may comprise anarray of 64 or 128 electrodes. DBS in selected brain regions hasprovided remarkable therapeutic benefits for otherwisetreatment-resistant movement and affective disorders such as chronicpain, Parkinson's disease, tremor and dystonia. DBS surgery aims toelectrically stimulate a target structure, while minimizing detrimentalside-effects caused by stimulation of particular nearby neuronalstructures. To make that possible, it is important to know the effect ofparticular stimulation settings on the electrical field that isgenerated in the brain tissue. Likewise, it is desirable to know whatstimulation settings to apply in order to obtain an optimal stimulationvolume.

In ‘Electric field and stimulating influence generated by deep brainstimulation of the subthalamic nucleus’ by McIntyre et al. (2004b), ClinNeurophys 115, 589-595, a method is disclosed for developing aquantitative understanding of the volume of axonal tissue directlyactivated by DBS of the subthalamic nucleus. The method uses finiteelement computer models (FEM) to address the effects of DBS in a mediumwith tissue conductivity properties derived from human diffusion tensormagnetic resonance data (MRI/DTI).

It is a disadvantage of the method of McIntyre et al. that an MRI/DTIsystem is needed for obtaining a conductivity map of the patient'sbrain. Additionally, DTI does not measure electrical conductivitydirectly but instead estimates one by assuming a theoreticalrelationship between water diffusion (measured by DTI) and electricalconductivity. Furthermore, the resolution of DTI for practical scanningtimes is limited to about 2 mm, i.e. 4 times the typical electrode pitchof high resolution DBS probes. It is also a problem that tissueconductivity changes over time, e.g. due to encapsulation of the probe,and that the known method requires a regular update of the conductivitymap. Performing regular DTI scans is unpractical for that purpose.

OBJECT OF THE INVENTION

In view of the above, it is an object of the invention to provide a morepractical or more accurate method for determining stimulation settingsfor a brain stimulation probe as described above.

SUMMARY OF THE INVENTION

According to a first aspect of the invention, this object is achieved byproviding a method for determining a relation between stimulationsettings for a brain stimulation probe and a corresponding V-field, thebrain stimulation probe comprising multiple stimulation electrodes, theV-field being a potential distribution in brain tissue surrounding thestimulation electrodes, the method comprising: sequentially applying atest current to n stimulation electrodes, n being a number between 2 andthe number of stimulation electrodes of the brain stimulation probe, foreach test current at one of the n stimulation electrodes, measuring aresulting excitation voltage at m stimulation electrodes, in being anumber between 2 and the number of stimulation electrodes of the brainstimulation probe, from the stimulation settings and the measuredexcitation voltages, deriving an (m*n) coupling matrix, an elementZ_(q,p) in the coupling matrix reflecting an amount of electricalimpedance between two of the stimulation electrodes and using thecoupling matrix for determining the relation between the stimulationsettings and the corresponding V-field.

Electrical properties, typically impedances, of the brain tissue closeto the electrodes are determined by applying the test currents andmeasuring excitation voltages. The coupling matrix comprises thedetermined electrical properties. An element Z_(q,p) in the couplingmatrix may, e.g., represent a ratio of the contribution to a voltageV_(q) on electrode q and a test current I_(p) injected in electrode p.These impedance values Z_(q,p) depend on properties of the stimulationprobe (e.g. electrode size, shape and material) and the surroundingsystem (e.g. brain tissue). It is to be noted that also the excitationvoltage at the stimulated electrode itself may be measured. Suchmeasurements will determine the diagonal elements in the (m*n) couplingmatrix and reflect an impedance between the stimulated electrode and aground electrode of the stimulation probe. The ground electrode orreturn electrode may be formed by the casing of the probe.

Alternatively, an impedance matrix Z may be generated by mathematicalinversion of an admittance matrix. The elements of the admittance matrixcan be determined by forcing a non-zero test voltage on a particularelectrode while forcing zero voltage on all other electrodes. Theelements of the admittance matrix are then obtained by measuring thecurrents in the electrodes necessary to create said voltages.

Using the information stored in the coupling matrix and some theoreticalknowledge about electrical fields, the relation between stimulationsettings and corresponding V-fields in the brain tissue are determined.Such a relation may, e.g., be provided in the form of a look-up tabledescribing the expected V-field for unit current excitation of thesingle electrodes. Based on this relation and assuming a linear system(in a linear system, the superposition theorem, known from networktheory, may be applied), it is then possible to calculate an expectedV-field (I) for any possible combination of stimulation currents appliedand, vice versa, to calculate the required combination of stimulationcurrents to obtain a target V-field.

Resulting V-fields in the brain tissue may, e.g., be determined usingknowledge of the expected currents I=(I₁, I₂, I₃, . . . , I_(m)) orpotentials V=(V₁, V₂, V₃, . . . , V_(m)) at each electrode of thestimulation probe. In a similar way, it may be calculated what currentsI or electrode potentials V are needed for obtaining target V-field inthe brain tissue. A relation between the electrode potentials V orcurrents I and the stimulation settings is derivable from the couplingmatrix.

The main advantage of the method according to the invention is that itdoes not require imaging devices for deriving electrical properties fromanatomical images. According to the invention, the electrical propertiesof the brain tissue are derived from the impedance measurements and noelectrical properties have to be determined indirectly, by analyzinganatomical images. The fact that no imaging apparatus is needed fordetermining the relation between the stimulation settings and thecorresponding V-field makes it much easier to update the relation overtime. Updating the relation may, e.g., be needed because tissueconductivity may change due to encapsulation of the probe. Furthermore,the method according to the invention may be used to provide moreaccurate estimations of required stimulation settings and/or expectedV-fields. The resolution of known imaging techniques like DTI is about 4times the typical electrode pitch of the stimulation probe, while themethod according to the invention provides detailed information on theelectrical properties of brain tissue close to each separate stimulationelectrode.

According to a second aspect of the invention, a control system isprovided, comprising means for applying test currents to the stimulationelectrodes, means for measuring excitation voltages at the stimulationelectrodes and a processor arranged for performing the method accordingto the invention.

These and other aspects of the invention are apparent from and will beelucidated with reference to the embodiments described hereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings:

FIG. 1 schematically shows a stimulation probe with a plurality ofstimulation electrodes,

FIG. 2 shows a block diagram of a control system according to theinvention,

FIG. 3 shows a flow diagram of a method for determining a relationbetween stimulation settings for a brain stimulation probe and acorresponding V-field,

FIG. 4 shows a flow diagram of a method of determining an expectedV-field, and

FIG. 5 shows a flow diagram of a method of determining requiredstimulation settings for obtaining a target V-field.

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1 schematically shows a brain stimulation probe 10 with a pluralityof stimulation electrodes 11. It is to be noted that this is just aschematic drawing and the actual stimulation probe 10 used may be quitedifferent. What is important for the stimulation probe 10 used in themethod and system according to the invention is that it has a pluralityof stimulation electrodes 11 distributed over at least part of the probesurface. For example, an array of 64 or 128 electrodes is used.

FIG. 2 schematically shows a control system 20 for controlling the brainstimulation probe 10 of FIG. 1 . The stimulation probe 10 is coupled toa processor 23 via a pulse generator 21. The processor 23 determines andcontrols the stimulation settings to be applied to the stimulationelectrodes 11 for enabling proper functioning of the stimulation probe10. The pulse generator 21 provides the electrical signals, e.g.currents, to the individual stimulation electrodes 11, in accordancewith instructions from the processor 23. The processor 23 is alsocapable of receiving data and signals from the stimulation electrodes 11in order to obtain information about the functioning of the stimulationprobe 10 and its interaction with the environment. An impedancerecording means or voltmeter 22 is provided for measuring excitationvoltages at the electrodes 11 adjacent to or further away from anelectrode 11 receiving an electrical current. The processor 23 isfurther coupled to a memory 24 for storing, e.g., patient data andsoftware for controlling the system 20 and the method according to theinvention. The control system 20 may be coupled to a local or wide areanetwork (e.g. the Internet) for being able to exchange or share datawith other systems.

In an embodiment, the number of independent current sources (e.g. 4) togenerate stimulation is less than the number of electrodes (e.g. 64).The output of a single current source may be distributed to severalelectrodes simultaneously. The current of the common source isdistributed over the electrodes in dependence of individual electrodestissue impedance and lead-impedance to the individual sites. Stimulationsettings may be defined as current generator current values combinedwith connection settings, i.e. to which electrodes the pulse generatorsare connected. Knowing the stimulation settings of electrodes to thecurrent sources and using the coupling matrix the stimulation currents I(on all electrodes) may be calculated.

Additionally, a display 26 may be coupled to the processor 23 forshowing information that may help a user with configuring or using thesystem 20. The system 20 may additionally comprise user input means,such as a mouse 25 or other type of pointer device and/or a keyboard.The display 26 may also be used for providing a graphical user interfacefor enabling a user to configure and control the system 20. For thatpurpose, the display 26 might also have touch screen functionality.

FIG. 3 shows a flow diagram of a method for determining a relationbetween stimulation settings for a brain stimulation probe 10 and acorresponding V-field. The method starts with an excitation step 31 inwhich the pulse generator 21 is used for sequentially exciting eachstimulation electrode 11 or a sub-group of selected stimulationelectrodes 11 with a known test current, I_(test). When a test pulse isapplied to one of the stimulation electrodes 11, the impedance recordingmeans or voltmeter 22 measures an excitation voltage at said electrode11 and response voltages at other stimulation electrodes 11 in responserecording step 32. The response may be recorded as electrode voltageV_(q,p) at the stimulation electrode q due to excitation at electrode por as measured impedance value Z_(q,p). This measurement may beperformed for all stimulation electrodes 11 or for a number m ofselected, e.g. neighboring, stimulation electrodes 11. After exciting afirst stimulation electrode 11 and measuring the responses on the inelectrodes 11, a subsequent stimulation electrode 11 may be tested. Whenn electrodes are excited and voltages are recorded on in electrodes, thefirst two steps 31, 32 are performed at least n times. Optionally, someor all stimulation electrodes 11 are tested twice or more, possibly withdifferent test currents, I_(test). The result of response recording step32, is m*n measurements of combined electrical properties of the probe10 and the tissue surrounding the probe 10. In matrix generating step33, this information may be processed to form an m*n coupling matrix 35.

In practice, the number of tested electrodes, n, will often equal thenumber of recording electrodes, m. This coupling matrix 35 captures theeffects of the inhomogeneous anisotropic tissue conductivity, i.e. itselements reflect the amount of electrical tissue impedance betweenvarious sites. For example, an entry (q,p) in the coupling matrix 35 mayhold the ratio of the voltage on electrode q and the current injectedinto electrode p. In a preferred embodiment, also the excitation voltageat the stimulated electrode itself is be measured. Such measurementswill determine the diagonal elements in the (m*n) coupling matrix andreflect an impedance between the stimulated electrode and a groundelectrode of the stimulation probe. The ground electrode or returnelectrode may be formed by the casing of the probe.

With the coupling matrix 35 it is possible to determine a pattern ofexpected electrode voltages Vat each of the electrodes 11 in response toa particular pattern of stimulation currents I. Similarly, it ispossible to determine the required pattern of stimulation currents Ineeded to obtain a desired pattern of electrode voltages V.

For proper operation of the probe 10 it may not yet be enough to knowwhat electrode potentials V are caused by what stimulation currents Iand vice versa. In step 34 of FIG. 3 , the coupling matrix 35 is used tocalculate an expected potential distribution (V-field) in the braintissue for a given pattern of stimulation currents or to calculate arequired stimulation pattern to obtain a desired V-field. Calculatingthe V-field from individual electrode potentials V or currents I may,e.g., be done using finite element modeling (FEM) or other numericaltechniques. The V-field may be calculated under the assumption ofhomogeneous tissue conductivity, but is preferably corrected by measureddata available from the coupling matrix 35. The relation 36, 37 betweenindividual electrode potentials V or currents I and the V-field alsodepends on the composition of the brain tissue. The coupling matrix 35comprises information about this composition and may thus be used toprovide a more accurate determination of the relation between V-fieldand electrode potentials V or currents I.

FIGS. 4 and 5 show exemplary flow diagrams of methods for realizing step34 in FIG. 3 . In these methods the coupling matrix 35 and the knowledgeabout the relation between individual electrode currents I and theV-field are used to determine required stimulation settings or expectedV-fields. FIG. 4 shows a method of determining an expected V-field andFIG. 5 shows a method of determining required stimulation settings forobtaining a target V-field.

In FIG. 4 it is shown how an expected V-field is calculated for aparticular set of stimulation settings. First the stimulation settingsare provided (step 41), e.g. in the form of pulse generator currents andconnections settings for the electrically coupling of the n electrodes11 to the pulse generators. Then, the coupling matrix 35 is used fordetermining (step 42) the resulting currents I₁, I₂, . . . , I_(q), . .. , I_(m) at the electrodes 11. When the electrode currents I₁, I₂, . .. , I_(q), . . . , I_(m) at the electrodes 11 are known, the relation 36between electrode currents I=I₁, I₂, . . . , I_(q), . . . , I_(m) andV-field is used for calculating (step 43) the resulting V-field. It isto be noted that the coupling matrix 35 is obtained using measurementsas described above with reference to FIG. 3 . The coupling matrix for animplanted probe 10 has at least to be determined once. However, thecoupling matrix 35 is preferably updated periodically in order to takeinto account the changes, e.g., in the brain tissue that may occur overtime. The relation 36 between electrode currents I and V-field may becomputed once under the assumption of homogeneous tissue conductivity,but is preferably corrected by measured data available from the couplingmatrix 35. The relation 36 may be updated together with the couplingmatrix 35.

In FIG. 5 it is shown how the stimulation settings are determined whichare needed for obtaining a target V-field. First a description of thetarget V-field is provided (step 51), e.g. in the form of a set ofcoordinates of positions target structures in the brain, which targetstructures are to be stimulated. Alternatively (or additionally),coordinates are provided describing positions of neuronal structures forwhich stimulation should be avoided. Then the relation 37 between theV-field and individual electrode currents I is used to calculate (step52) the electrode currents I needed to obtain the desired V-field. Usingthe coupling matrix 35, the stimulation settings for obtaining theserequired electrode currents I are then determined (step 53).

It will be appreciated that the invention also extends to computerprograms, particularly computer programs on or in a carrier, adapted forputting the invention into practice. The program may be in the form ofsource code, object code, a code intermediate source and object codesuch as partially compiled form, or in any other form suitable for usein the implementation of the method according to the invention. It willalso be appreciated that such a program may have many differentarchitectural designs. For example, a program code implementing thefunctionality of the method or system according to the invention may besubdivided into one or more subroutines. Many different ways todistribute the functionality among these subroutines will be apparent tothe skilled person. The subroutines may be stored together in oneexecutable file to form a self-contained program. Such an executablefile may comprise computer executable instructions, for exampleprocessor instructions and/or interpreter instructions (e.g. Javainterpreter instructions). Alternatively, one or more or all of thesubroutines may be stored in at least one external library file andlinked with a main program either statically or dynamically, e.g. atrun-time. The main program contains at least one call to at least one ofthe subroutines. Also, the subroutines may comprise function calls toeach other. An embodiment relating to a computer program productcomprises computer executable instructions corresponding to each of theprocessing steps of at least one of the methods set forth. Theseinstructions may be subdivided into subroutines and/or be stored in oneor more files that may be linked statically or dynamically. Anotherembodiment relating to a computer program product comprises computerexecutable instructions corresponding to each of the means of at leastone of the systems and/or products set forth. These instructions may besubdivided into subroutines and/or be stored in one or more files thatmay be linked statically or dynamically.

The carrier of a computer program may be any entity or device capable ofcarrying the program. For example, the carrier may include a storagemedium, such as a ROM, for example a CD ROM or a semiconductor ROM, or amagnetic recording medium, for example a floppy disc or hard disk.Further the carrier may be a transmissible carrier such as an electricalor optical signal, which may be conveyed via electrical or optical cableor by radio or other means. When the program is embodied in such asignal, the carrier may be constituted by such cable or other device ormeans. Alternatively, the carrier may be an integrated circuit in whichthe program is embedded, the integrated circuit being adapted forperforming, or for use in the performance of, the relevant method.

It should be noted that the above-mentioned embodiments illustraterather than limit the invention, and that those skilled in the art willbe able to design many alternative embodiments without departing fromthe scope of the appended claims. In the claims, any reference signsplaced between parentheses shall not be construed as limiting the claim.Use of the verb “comprise” and its conjugations does not exclude thepresence of elements or steps other than those stated in a claim. Thearticle “a” or “an” preceding an element does not exclude the presenceof a plurality of such elements. The invention may be implemented bymeans of hardware comprising several distinct elements, and by means ofa suitably programmed computer. In the device claim enumerating severalmeans, several of these means may be embodied by one and the same itemof hardware. The mere fact that certain measures are recited in mutuallydifferent dependent claims does not indicate that a combination of thesemeasures cannot be used to advantage.

The invention claimed is:
 1. A method for determining a relation betweenstimulation settings for a brain stimulation probe and a correspondingV-field, the brain stimulation probe comprising multiple stimulationelectrodes, the V-field being a potential distribution in brain tissuesurrounding the stimulation electrodes, the method comprising:sequentially applying a test current to n stimulation electrodes, nbeing a number between 2 and the number of stimulation electrodes of thebrain stimulation probe; for each test current at one of the nstimulation electrodes, measuring a resulting excitation voltage at mstimulation electrodes, m being a number between 2 and the number ofstimulation electrodes of the brain stimulation probe; from thestimulation settings and the measured excitation voltages, deriving an(m*n) coupling matrix, an element V_(q,p) in the coupling matrixreflecting an amount of voltage between two of the stimulationelectrodes, using the coupling matrix to determine the relation betweenthe stimulation settings and the corresponding V-field; forcing anon-zero test voltage on one of the stimulation electrodes while forcingzero voltage on all other stimulation electrodes; measuring resultingcurrents in the electrodes necessary to create said forced non-zero testvoltages; determining an admittance matrix, the elements of theadmittance matrix reflecting the measured resulting currents; andgenerating the coupling matrix by mathematical inversion of theadmittance matrix.
 2. A method for determining a relation betweenstimulation settings for the brain stimulation probe and thecorresponding V-field as claimed in claim 1, the method furthercomprising: receiving a predetermined set of stimulation settings; andusing the relation between the stimulation settings and thecorresponding V-field for determining the V-field corresponding to thepredetermined set of stimulation settings.
 3. A method for determining arelation between stimulation settings for the brain stimulation probeand the corresponding V-field as claimed in claim 1, the method furthercomprising: receiving a description of a target V-field; and using therelation between the stimulation settings and the corresponding V-fieldfor determining a set of required stimulation settings for obtaining thetarget V-field.
 4. A computer program product for determining a relationbetween stimulation settings for the brain stimulation probe and thecorresponding V-field, which program is operative to cause a processorto perform the method as claimed in claim
 1. 5. A control system fordetermining a relation between stimulation settings for a brainstimulation probe and a corresponding V-field, the brain stimulationprobe comprising multiple stimulation electrodes, the V-field being apotential distribution in brain tissue surrounding the stimulationelectrodes, the control system comprising: a test current applicationmodule applying test currents to the stimulation electrodes; ameasurement module measuring an excitation voltage resulting from theapplied test currents; and a processor being arranged to: instruct thetest current application module to apply test currents to sequentiallyapply a test current to n stimulation electrodes, n being a numberbetween 2 and the number of stimulation electrodes of the brainstimulation probe; instruct the measurement module to measure excitationvoltage to measure at m stimulation electrodes an excitation voltagecaused by each test current, m being a number between 2 and the numberof stimulation electrodes of the brain stimulation probe; from thestimulation settings and the measured excitation voltages, deriving an(m*n) coupling matrix, an element V_(q,p) in the coupling matrixreflecting an amount of voltage between two of the stimulationelectrodes: using the coupling matrix for determining the relationbetween the stimulation settings and the corresponding V-field; forcinga non-zero test voltage on one of the stimulation electrodes whileforcing zero voltage on all other stimulation electrodes; measuring theresulting currents in the electrodes necessary to create said forcedvoltages; determining an admittance matrix, the elements of theadmittance matrix reflecting the measured resulting currents; andgenerating the coupling matrix by mathematical inversion of theadmittance matrix.